Rasagiline, represented by structural formula (1) and chemically named 1-(R)-(2-propynylamino)indan, is a selective and potent irreversible monoamine oxidase type B (MAO-B) inhibitor. It is currently marketed, as the mesylate salt, for the treatment of Parkinson's Disease (PD), both as monotherapy and as adjunct therapy to levodopa. Rasagiline (1) may also be useful for the treatment of dementia, Alzheimer's Disease, depression, hyperactive syndrome, stroke, brain ischemia, neurotrauma, schizophrenia and multiple sclerosis.

Rasagiline (1) was first described in U.S. Pat. No. 5,457,133, in which the method of its preparation is a single step process comprising reacting (R)-1-aminoindan (2) with propargyl chloride. The reaction is carried out in acetonitrile with potassium carbonate at a temperature of 60° C. for 16 hours.
The preparation of (R)-1-aminoindan (2) is disclosed in an article by Lawson and Rao in Biochemistry, vol. 19, pages 2133-2139, 1980, in which racemic 1-aminoindan is resolved via fractional crystallization of its diastereomeric salt with L-malic acid in ethanol. However, the purification procedures disclosed are difficult and time consuming and do not afford very pure product.
The preparation of (R)-1-aminoindan (2) is also disclosed in EP 235590, in which racemic 1-aminoindan is resolved via fractional crystallization of its diastereomeric salt with the expensive resolving agent D-N-acetyl-3,4-dimethoxyphenylalanine in methanol. However, again the purification procedures disclosed are difficult, time consuming and do not afford very pure product.
U.S. Pat. No. 5,994,408 discloses a method for the preparation of (R)-1-aminoindan (2) via resolution of N-benzyl-1-aminoindan using (S)-mandelic acid. However, this process is long and involves multiple protection/deprotection steps and, again, the purification procedures disclosed are difficult, time consuming and do not afford very pure product.
Another process for the preparation of rasagiline (1) via (R)-1-aminoindan (2), disclosed in patent application WO 02/068376, involves the preparation of N-benzyl-1-aminoindan from indanone or 1-chloroindan and benzylamine. Resolution of N-benzyl-1-aminoindan using L-tartaric acid and catalytic hydrogenolysis to remove the benzyl group affords (R)-1-aminoindan (2), which is further converted to rasagiline (1) by reaction with propargyl chloride. This process suffers from the drawback of having many steps including protection and deprotection, and the overall yield for the preparation of (R)-1-aminoindan (2) was reported to be a very low 19%.
An alternative process for the preparation of rasagiline (1), disclosed in patent application WO 95/11016, involves reaction of racemic 1-aminoindan with propargyl benzenesulfonate in the presence of 15% aqueous NaOH in toluene to form racemic rasagiline. The racemic rasagiline is then resolved to form rasagiline (1) via fractional crystallization of its diastereomeric salt with L-tartaric acid. However, the reported process is low yielding and affords an impure product.
US 2006/0199974 discloses a process which involves asymmetric reduction of indanone to (S)-indanol followed by conversion to the corresponding tosylate which undergoes coupling with propargylamine to afford rasagiline (1). The overall yield was reported as 66%. This process is economically and commercially not suitable as an expensive catalyst is used for the asymmetric reduction.
Therefore the prior art processes for the preparation of rasagiline (1) can be classed into three main categories: firstly, reaction of (R)-1-aminoindan (2) with a propargyl alkylating agent; secondly, reaction of racemic 1-aminoindan with a propargyl alkylating agent followed by resolution of the racemic rasagiline formed; and thirdly, longer chemical syntheses involving resolution or stereospecific synthesis of different intermediates.
For the commercial preparation of rasagiline (1) and its pharmaceutically acceptable salts, the first approach is the most efficient in principle. The second and third approaches suffer from the disadvantages of using expensive reagents; being multi-step, long processes; being low yielding; and/or producing impure products which require substantial purification. However, although the first approach is the most attractive in principle, the reported processes following this general approach are not very efficient and do not give a high yielding, economically and commercially viable process for generating the required enantiomerically pure (R)-1-aminoindan (2).
In view of the above disadvantages associated with the prior art, there is a need for an improved process for the preparation of enantiomerically pure (R)-1-aminoindan (2) which does not involve multiple steps, uses relatively inexpensive reagents, eliminates the need for cumbersome purification techniques, is economical and high yielding, and which provides (R)-1-aminoindan (2) with a high degree of purity.
As the commercial production of rasagiline (1) and rasagiline mesylate are of great importance and in view of the above disadvantages associated with the prior art, there is a real need for alternative and improved processes for the preparation of rasagiline (1) and rasagiline mesylate which do not involve multiple steps and further eliminate the need for cumbersome purification techniques. The alternative processes must be economical and high yielding and provide rasagiline (1) and rasagiline mesylate with a high degree of chemical and optical purity.